Sufentanil vs fentanyl for fast-track cardiac anaesthesia.

SUMMARY
A perioperative anaesthetic management that aims to facilitate tracheal extubation of patients within 1-6 hrs after cardiac surgery is called "fast-track". Main advantage of "fast-track" method is better usage of medical resources and lowering hospital costs without increasing morbidity and mortality of the patients. Standard fast-track protocols contain short acting anaesthetic agents, smaller incisions and decreased pump times without hypothermia. In this study we compared two short acting opioid drugs, fentanyl versus Sufentanil when used as a part of the balanced anaesthesia technique for fast track in cardiac surgery patients & evaluated the time taken for extubation, haemodynamic stability, analgesia requirements & incidence of awareness. The results from the study show that both agents provide good haemodynamic stability and postoperative analgesia. Although Sufentanil provides earlier extubation, both agents reduce the ICU stay equally. In conclusion both agents can be used effectively for fasttrack cardiac anaesthesia.


Introduction
Opioids have beenan integralpart of cardiac anaesthesiadue to their cardiostableproperties. Prolonged mechanical ventilation as a consequence of high dose opioid anaesthesia was an essential part of postoperative care in cardiac surgeryduringits developing years.
A perioperativeanaesthetic managementthat aims to facilitate trachealextubation of patients within 1-6 hrs after cardiac surgeryis called 'fast-track 1,2 (FTCA).Main advantageof "fast-track"method isbetter usageof medicalresourcesand loweringhospitalcostswithoutincreasing morbidity and mortality of the patients. Safety and effectiveness of fast-track versus slow-track cardiac anaesthesia is proved by many studies. [3][4][5] An effective fast track cardiac anaesthesia program requires appropriate selection of suitable patients, a low dose opioid anesthetic technique,early tracheal extubation, a short stay in the ICU, and coordinatedperioperative care. 6,7 In this study we compared the time to extubation, haemodynamic stability and postoperative analgesia whentwo shortactingopioiddrugs, fentanylorsufentanil were used asa partof the anaesthesia technique for fast trackin cardiac surgery patients. We also compared incidence of awareness associated with FTCA.

Methods
After obtainingapproval from hospital academic and ethics committee and written, informed valid consent, 100 patients between the age of 15-50 years, undergoingelective open-heart surgery for valvular and simple congenital heart disease were enrolled in this randomized, prospective, double blinded study. The study excludedpatients withleft ventricularejection fraction (LVEF) <20%, severe pulmonary hypertension (PH), severe COPD, renal insufficiency, severe liver disease, history of seizure or stroke, history of allergy to propofol, patientsin whom cardiopulmonary bypass (CPB) time >2 hrs and pregnant patients.
All patients underwent thorough preoperative evaluation and investigations.All the cardiac medications of the patient were continued until the morning of surgery. After arrival to the operating room, patients were administered oxygen (O 2 ) by nasal prongs and monitoring of ECG (5 lead) with automated ST segment analysis and pulse oximetry was initiated (IntellivueMP 40,Philips MedicalSystems, Germany). Under local anaesthesia and aseptic precautions, a 16-G intravenous cannula was inserted in the dorsum of right hand, a 20-G intra-arterial cannula was introduced into the left radial artery for monitoring of the arterial pressure and obtainingarterial blood for analysisand right internaljugularvein cannulationwas done with appropriate size triple lumen cannula for CVP monitoring.
Patients were randomly divided into two groups of 50 patients each. Sufentanil group (S) received 0.5µg.kg -1 of sufentanil while Fentanyl group (F) received 3µg.kg -1 of fentanyl as part of induction. All patients were induced with IV midazolam 0.05mg.kg -1 , a sleep dose of thiopentone sodium and IV vecuronium 0.1mg.kg -1 to facilitate endotracheal intubation. Patients were mechanically ventilated with tidal volume of 10 ml.kg -1 and respiratory rate of 10-12 / minusing Penlon ventilator. Anasogastric tube and nasal temperature probe were introduced. Diclofenac suppository was inserted. Anaesthesiawas maintained using oxygen, nitrous oxide, isoflurane (end tidal concentration 0.8-1%) and intermittent doses of vecuronium, and midazolam (1-5mg) before and after cardio-pulmonary bypass with goal to maintain stable haemodtnamics. On cardiopulmonary bypass,an infusion of propofol was started at the rate of 4-5 mg.kg -1 .hr -1 for maintenanceof anaesthesia.Additional doses of opioid drug were given at the following steps of intense stimulus-at sternotomy, just before going 'ON' CPB, coming 'OFF' CPB and as & when required as per the discretion of consultant anaesthetist. Patients from Sufentanilgroup received0.1 µg.kg -1 of Sufentanil while patients from Fentanyl group received 1µg.kg -1 of fentanyl as additional dose. Total amount of sufentanil, fentanyland midazolam administered during entire procedure was restricted to 1 µg.kg -1 , 6 µg.kg -1 and 5mg respectively.
Inspired and expired gas concentration of O 2 , carbon dioxide (CO 2 ) and isoflurane were measured using anaesthetic gas monitoringsystem (anaesthesia gas monitor, Intellivue MP 40, Philips Medical Systems, Germany). Haemodynamic parameters were maintained within 20% of the basal values with small boluses of IV nitro-glycerine/ sodium nitroprusside or IV ephedrine / phenylephrine and small boluses of IV metoprolol/ esmololor atropine / glycopyrolate as required. Fillingpressures and fluid balance was main-tainedusinglactatedRingers solution,6%hydroxy-ethyl starch (HAES-steril, Fresenius Kabi) and blood and blood products as necessary. All patients were given infusion of 5% glucose with 10 units of insulin and 20 mEq of potassium for myocardial protection.All the cardiac surgeries were done usingnormothermic cardiopulmonary bypass.
If needed, infusions of dopamine/ isoprenaline/ adrenaline were used as inotrope while coming off bypass to maintain hemodynamics as per choice of anaesthetist and surgeon. Chest wound and chest tube insertion sites were infiltrated with 0.25% bupivacaine, in all patients.
At the end of surgery, patients were reversed and extubated on table if  Awake & alert  Hemodynamically stable or minimalinotropic support  Good tidal volume with a respiratory rate of 10-24 breaths /min and good cough reflex.
Patientswere mechanically ventilated when  Deeply sedated patient  Unstable hemodynamics or high dose inotropic support The mode of ventilation in allpatients was as follows  Synchronised intermittent mandatory ventilation (SIMV) + Pressure support ventilation(PSV) ( Patients who were deeply sedated did not require additionalsedatives or relaxants. Muscle relaxant was given only to patients with unstable hemodynamics or heavy inotropic support to reduce work of breathing tillhaemodynamically stable.
These ventilated patients were weaned by standard protocol when hemodynamically stableand were extubated with or without reversal dependingon clinicalsigns of residualneuro -muscularblockade. Patients requiring prolonged ventilation due to surgical complications such as excessivedrains, need for reexploration were excluded from the study. 'Ventilator time' was defined as time from arrival in ICU to extubation. Prolonged ventilation was defined as continued mechanical ventilation till next day morning or for more than 12 hours.All patients were given IV ondansetron 0.8 mg.kg -1 before extubation.
All patients were monitored in ICU postoperatively every 15 min for first hour and then every half an hour for 6 hours. Patients were asked to rate his/her pain (0-10) using VisualAnalogue Score 30 minutes after extubation and at next morning. IV tramadol was given (1mg.kg -1 ) as rescue analgesia. In awake and extubated patients trtmadol was given if VAS> 4cm or when patient demanded an analgesic. In mechanically ventilated patients, tramadol was given on clinical evidence of pain e.g. sweating, tachycardia, and hypertension.
Time of first dose of tramadolwas noted and the number of doses of tramadol between arrival in ICU and next morning were also noted. Patients were also asked for awareness during surgery, one hour after extubation and atnext morning.Each patient was asked a standard set of questions. 1. What is the last thing you rememberbefore surgery?2. Whatis thenext thing you remember? 3. Can you remember anythingin be-tween these two periods? 4. Did you have any dreams in between these two periods?
Sample size was calculated from previous study 8 on the basis of the anticipated difference in mean ventilationtime betweenthe two groups. Assuming Type I error of 5% and Type II error of 20% (Power 80%), a 30% reduction was considered as clinically significant i.e. to detect difference of 120 minutes with standard deviation of 202minutes. This required a sample size of 45 patients in each group. We used 50 patients in each group.
The data obtained in this study was analyzed using either unpaired't' test or Pearson Chi-Square test according to different variables. A p value of less than 0.05 was considered significant.

Results
A totalof 100patients were included in this prospective, randomized double blind study with 50 patients in each group. The two groups were comparable with regard to the demographic, preoperative and intraoperative data ( Table 1,2) Allthepatients from both groupsmaintained stable haemodynamics throughout thesurgery andthere was no statisticaldifference in the vitalparameters between the two groups in the prebypass and postbypass period. There was no statistically significant difference in thenumber of patients needinginotropic supportas well as the amount of inotropic support needed between the two groups in postbypass period.
The VAS score after extubation was 0.54 + 1.417 cm in Sufentanil group and 0.32 +1.115 mm in Fentanyl group. The VAS score on the next day morning was 0.46 + 0.734 cm and 0.42+ 0.642 cm in Sufentanil and Fentanyl groups respectively. These VAS scores were statistically comparable in the two groups ( Table  3). The time to first dose of analgesic was significantly less (43.70 + 51.145 min) in Sufentanilgroup as compared to Fentanyl group (70.68 + 65.538 min), however the totalnumber of doses needed till the next day   (Table 4).
Thirty -two out of fifty patients (64%) from the Sufentanil groupcould be extubated on table while from Fentanyl group, 19 patients (38%) could be extubated on table. Out of the 18 patients from Sufentanil group needing mechanicalventilation, theindication was deep sedation in 13 patients and heavy inotropic support in 5 patients. Out of the 31 patients from Fentanyl group needing mechanicalventilation, theindication was deep sedation in 20 patients and heavy inotropic support in 11 patients. The mode of ventilation in all patients was SIMV + PSV (10 cmH2O) + CPAP (3-5 cmH2O) with TV 10 ml/kg & RR 10 breaths /min. This difference in the number of patients needing mechanicalventilation and the ventilation time was statisticallysignificant. However, this difference in ventilation time did not affect the duration of ICUstay which was 1.16 + 0.370 days in Sufentanilgroup and 1.14 + 0.351 days in Fentanyl group which was comparable (Tables 5-6).   Only one patient out of hundred belonging to Sufentanilgroup had awareness in the form of explicit memory of sound of sternotomy which lasted for few seconds. This patient was referred for psychological counseling.

Table 4 Statistical analysis and comparison of time (min) for first dose of Tramadol and number of Tramadol doses between the two groups
None of the patients from either group had vomiting in postoperative period. One patient from Fentanyl group complained of mild nausea. This low incidence of PONV could have been because:i)Allpatientswere givenantiemetic prophylaxisprior to extubation in theform of Inj.Ondansetron 0.8mg/kg. ii) We did not use very high doses of opioids. iii) Local anaesthetic infiltration of the surgicalsite reduced requirement of Inj.Tramadol

Discussion
Conventional practice of cardiac anaesthesia included high dose of opioid agents and prolonged post operativeelective mechanicalventilation which in turn led to prolonged ICU stay and a protracted recovery. With the advent in surgicaltechnique, warm bypass and anaesthesia; "Fast-Tracking" has become areality. Fast -Trackingincorporates early extubation leadingto early mobilization and rehabilitation of patients 9 . Early extubation improves cardiac performance due to increased ventricular filling and reduces the incidence of postoperative pulmonary complications such as atelectesis. 9 Early mobilization has also been shown to improve patients' emotionalwell being. Fast trackingalso shortens ICU and effectively hospital stay resulting in reduction of costand betterresource utilization 5 .A growing body of evidence fromrandomizedtrials hasidentified many anesthetic interventions inFast Track cardiac anaesthesia (FTCA) that can improve outcome after cardiac surgery 10 . These includenew short-acting hypnotic, opioid, and neuromuscular blockingdrugs. Fentanyl, Sufentanil, Remifentanilhave been used effectively for FTCA in many studies. [4][5][6][7] Sufentanil is 5-10 times more potent than Fentanyland has a shorter duration ofaction than Fentanyl. Wehypothesized that Sufentanil would shorten the time for extubation and ICU stay.
The purposeof this study was to compare the effects of two different opioid drugs Fentanyl and Sufentanil for cardiac surgery with respect to time to extubation, postoperative pain,hemodynamic stability and time to intensive care unit discharge and awareness during surgery. This was a prospective, randomized double blind study of100patients,50in each group labeled as GROUP 'S' and GROUP 'F' (another two patients wereexcluded fromstudy becauseof prolonged ventilation >6 hrssecondary to surgical complication).
3µg.kg -1 of fentanyl was used duringinduction in 'F'group. As sufentanil is 5-10times more potent than Fentanyl with half the duration of action, loading dose of 0.5µg.kg -1 of sufentanilwas used for induction in 'S' group. For subsequent doses, 1µg.kg -1 of fentanyland 0.1µg.kg -1 of sufentanil was given respectively and the total dose fentanyland sufentanilwas restricted to 6 µg.kg -1 and 1 µg.kg -1 respectively. We used low doses of fentanyl and sufentanil compared to most studies in literature as the patient populationcomingto our setup with valvular or congenitalheart disease belongsto low socio-economic society with poor general condition and this dose range was found to be adequate in pilot cases.
There was no statistically significant difference in the two groups with respect to age, weight, sex and in percent distributionof diagnosisamongthe two groups. Thus both the groups were comparable with respect to demographic parameters and surgicaldiagnosis. There was no statistically significant difference in the preoperative hemodynamic parameters making the two groups comparable in terms of baseline parameters.
Throughout the prebypass and postbypass period hemodynamic parameters, SpO 2 andtemperature were monitored every 5 min. There wasno statistically significant difference in these parameters in both the groups throughout prebypass and postbypass period. Therewas no statistically significantdifference between twogroups inthe numberof patientsneedingionotropic support as well as the dose of ionotropic agent. Thus both Sufentanil and Fentanyl provide good hemodynamic stability.
More number of patients in Sufentanilgroup (32 i.e.64%) could be extubated on table and did not need mechanical ventilation as compared to 19 patients (i.e.38%)in Fentanylgroup. Themean time of mechanical ventilation was 63.10 min in Sufentanil group as compared to 119.90min in Fentanyl group. Thus, time for mechanicalventilation inSufentanilgroupwas found to be reduced than that in Fentanylgroup by an average of 57 minutes. This difference in the number of patientsneeding mechanicalventilation and duration of mechanical ventilation was statistically significant, indicating that extubation is achieved earlier in Sufentanil group. However,thisdifference didnot affectthe length of ICU stay which was comparable in both groups.
Our results are similar to those of Butterworth, John MD; James, Robert Stat et al 11 who found that use of Sufentanil rather than Fentanylwas associated with a significant (p = 0.045) reduction (of 1.9 h 95% CI, 0.04 to 4.1 h) in duration of time to extubation and no significanteffect on ICUlength of stay after extubation.
London MJ, 12 did recent observational study of Butterworth et alusing "mixed-effects" logistic regression modeling of a 40 hospital"benchmarking" dataset, and found little effect of use of Sufentanil (over Fentanyl) on ICU or total length of stay (after adjustment for patient risk and hospital level effects) but, Sufentaniluse was associated with a 1.9 hr. reduction in time to extubation. Our results are similar.
In our study, no statistically significant difference was found between two groups with regards the VAS score after extubation and VAS on the next day morning or after 12hours. In terms of the time for first dose of Tramadol required, it was found to be earlier with Sufentanil than Fentanyl 43.70±51.145 min vs.70.68±65.538 min; which is statistically significant. This is obvious as Fentanyl has longer duration of action compared to Sufentanil. But the total doses of Tramadolrequired in the post operative period till next morning were similar. Engoren et al 13 studied patients undergoingcardiac surgery which were randomized to a Fentanyl-based, Sufentanil-based, or remifentanilbased anesthetic. Postoperative pain was measured at 30 min after extubation and at 6:30 AM on the first postoperative day. Pain scoresat bothtimes weresimilar in all three groups (P > 0.05).
Cardiac anaesthesia is associated with higher incidence of awareness compared with other specialties. The incidence reported ranges from 1.1% to 23% dependingupon the dose andagents usedin anaesthesia. Possible reasons for this are, use of high opioid based techniques which reduces requirement of inhalational and intravenous anesthetic agents, almost unpredictable pharmacodynamics of anaesthetics under the extracorporeal circulation especially in the rewarming period and at the time of cessation of bypass, interpersonal and interracial differences in drug reactions, haemodilution, and bindingon foreign surface areas.
Dowd et al 14 did a prospective study on incidence of awareness in cardiac anaesthesia and reported an incidence of 0.3% in fast-track cardiac anaesthesia. This low incidence of awareness was related to the use of a balanced anesthetic technique involvingthe continuous administration of volatile (isoflurane) or intravenous (propofol) anaesthetic agents before, during, and after cardiopulmonarybypass. We too, used a balancedanesthetic technique.
In our study, one case from Sufentanilgroup had awareness duringanaesthesia.The overallincidence of awareness in our study was 1.7% which was statistically insignificant. We did not use a BIS monitor and incidence of awareness in our study could have been probably avoided usingBIS monitor.
In conclusion, both sufentanil and fentanylprovide hemodynamic stability, early recovery and equal VAS scores in postoperative period, though fentanyl provides longer duration of postoperative analgesia. Sufentanilallows earlier extubationbut duration of ICU stay is similar with both drugs. There is no statistically significant difference in incidence of awareness in the two groups. Thus, both theagents can be usedfor Fast-Track cardiac anaesthesia (FTCA), effectively. A use of BIS monitor is advisable to prevent awareness.